2-Nitro-3-phenylbenzofuran alkanoic (or propenoic) acids

ABSTRACT

Optionally substituted 2-nitro-3-phenylbenzofuranalkanoic and -alkenoic acids which are active as antimicrobial agents, processes for their preparation and intermediates therefor are described.

This is a continuation-in-part of application Ser. No. 724,717, filedSept. 20, 1976 and now abandoned, which is itself a continuation-in-partof application Ser. No. 616,277, filed Sept. 24, 1975 (now abandoned)with which Ser. No. 724,717 was copending.

FIELD OF THE INVENTION

This invention relates to a class of 3-phenylbenzofuran compounds whichare substituted on the 4, 5, 6 or 7 position of the benzo ring by alower alkanoic acid group or an ester, amide, acyl halide orpharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

3-Phenylbenzofuranalkanoic acids and -alkenoic acids and certainderivatives thereof have been reported, for example in U.S. Pat. Nos.3,682,976 and 3,862,134 as having anti-inflammatory activity. Thecompound 2-nitro-3-phenylbenzofuran has been reported, although nophysiological activity has been reported prior to the present invention.Certain neutral 2-nitrobenzofurans are known as antibacterial agents,for example, see French Patent 2,081,585 and several publications byRene Royer et al. Acidic compounds combining the structural features ofthe compounds of the present invention have not previously beendescribed.

SUMMARY OF THE INVENTION

The present invention relates to optionally substituted2-nitro-3-phenylbenzofuranalkanoic and -alkenoic acids and esters,amides, acyl halides and pharmaceutically acceptable salts thereof whichare active as antimicrobial agents.

It is therefore an object of the invention to provide compounds whichare active antimicrobial agents.

It is a further object of the invention to provide processes forpreparing the compounds of the invention.

It is a further object of the invention to provide a method forcontrolling microbes.

It is a further object of the invention to provide a method forcontrolling bacteria.

It is a further object of the invention to provide a method forcontrolling fungi.

It is a further object of the invention to provide a method forcontrolling protozoa.

It is a further object of the invention to provide a method forcontrolling trichomonads.

It is another object of the invention to provide antimicrobialcompositions containing 2-nitro-3-phenylbenzofuranalkanoic and -alkenoicacids and esters, amides, acyl halides and pharmaceutically acceptablesalts thereof as active ingredients therein.

It is another object of the invention to provide novel intermediates inthe preparation of the antimicrobial agents of the invention andprocesses using the novel intermediates to prepare the active agents.

Still other objects of the invention will be made apparent by thefollowing specification.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention there is provided a class ofcompounds of the formula: ##STR1## wherein X is halogen, lower alkyl,lower alkoxy, nitro, phenyl, cyano or trifluoromethyl, n is zero, one ortwo, R is straight or branched chain alkylene of one to four carbonatoms or ethenylene, Y is methyl, methoxy, halogen or hydrogen, or anester, amide, acid halide or pharmaceutically acceptable salt thereof.When n is zero, the indicated ring positions are unsubstituted. "Lower",when applied to substituent groups herein, refers to groups containingfrom one to four carbon atoms.

Thus, structurally, the compounds combine an alkanoic or alkenoic acidgroup, a benzofuran ring, a 2-nitro group on the benzofuran ring and a3-phenyl group on the benzofuran ring. The free acids are ordinarilywhite or yellowish to brown crystalline or amorphous materials whenpurified. They are substantially insoluble in water or aliphatichydrocarbons and are more soluble in lower alcohols, halogenatedsolvents, benzene, dimethylformamide and the like. The esters and amidesare generally somewhat more soluble in organic solvents. The alkalimetal salts have appreciable solubility in water and lower alcohols.

All of the compounds of the invention are active against bacteria andsome are also active against other microorganisms, including fungi andprotozoa, in vitro and topically. Thus, they can be used fordisinfecting and sterilizing, for example of medical and dentalequipment, as components of disinfecting solutions. The compounds areparticularly useful as antibacterial agents. In general, the compoundsare also active in vivo in animals. The free acids are presentlypreferred for many purposes due to their generally higher levels ofantimicrobial activity in vitro. For applications in which watersolubility is of importance, the salts are ordinarily used.

The compounds of the invention in which R is methylene (--CH₂ --) form apresently preferred subclass, due to their high in vivo activity. Otherpreferred subclasses (due to their high degree of antimicrobialactivity) are the compounds in which X is fluorine and/or chlorine andthe compounds in which the (4) position of the benzofuran moiety issubstituted by hydrogen. The preferred compounds are antimicrobial invitro and in vivo, are active when administered orally, and providedetectable and antimicrobially active blood levels in mammals. Some ofthem are active at concentrations of less than 1.0 μg/ml versusStaphylococcus aureus. The particularly preferred compounds (which havebroad spectra of antibacterial activity and good therapeutic ratios LD₅₀/ED₅₀) are:

2-nitro-3-phenyl-7-benzofuranacetic acid,

2-nitro-3-phenyl-6-benzofuranacetic acid,

2-nitro-3-phenyl-5-benzofuranacetic acid,

3-(4'-chlorophenyl)-2-nitro-5-benzofuranacetic acid,

3-(4'-fluorophenyl)-2-nitro-7-benzofuranacetic acid,

3-(4'-chlorophenyl)-2-nitro-7-benzofuranacetic acid,

2-nitro-3-phenyl-7-benzofuranacrylic acid,

2-nitro-3-phenyl-5-benzofuranpropionic acid and

2-nitro-3-phenyl-7-benzofuranpropionic acid.

Alkali metal, alkaline earth, aluminum, iron and other metal and aminesalts are often the equivalents of the corresponding acid-formcompounds, and offer advantages in solubility, absorption, persistence,formulation and the like. The salts are of interest for topical uses(e.g. opthalmic and dermatologic). Alkali metal salts (e.g. Na and K)are preferred. The esters and amides are also useful for modifyingsolubility, persistence, absorption and other properties. The esters ofthe invention include lower alkyl esters, hydroxyalkyl esters andN,N-dialkylaminoalkyl esters, glyceryl esters and alkoxyalkyl(particularly methoxymethyl) esters. The amides of the invention includeN-unsubstituted amides, N-alkylamides, N,N-dialkylamides,dialkylaminoalkylamides, quaternary ammonium alkylamides,bis(2-hydroxyethyl)-amides, amino acid amides e.g. alanine and glycineamides, carboxyphenylamides, piperazinyl amides, amino sugar amides,alkylsulfonamides, sulfoethylamides, sulfamoylphenylamides and5-tetrazolylamides.

Among the important subclasses of the compounds of the invention whichare represented by specific examples herein are those in which R ismethylene, ethylene, methylmethylene or dimethylmethylene; in which X ismethyl or methoxy; in which X is fluorine, chlorine or bromine; in whichn is one; and in which n is two, and one or both X moieties are halogen,methyl or methoxy. Important subclasses of the compounds other than thefree acids which are represented by specific examples herein are loweralkyl esters, hydroxyalkyl esters and N,N-dialkylaminoalkyl esters(particularly ethyl, hydroxyethyl and N,N-dimethylaminoethyl esters),N-unsubstituted amides, dialkylaminoalkylamides, amino acid amides,amino sugar amides and alkylsulfonamides. The ester and amide portionsof the compounds of the invention (which replace the OH of the carboxylfunction of the free acids) preferably contain not more than ten carbonatoms.

In compounds of the invention wherein R is branched, optically activecompounds are obtained which are included within the scope of theinvention.

The free acids of the invention are prepared by methods using knownstarting materials including:

A. the direct nitration of 3-phenylbenzofuranalkanoic and -alkenoicacids,

B. preparing an intermediate 2-halo-3-phenylbenzofuranalkanoic or-alkenoic acid by either (1) the specific halogenation of the 2 positionof a 3-phenylbenzofuranalkanoic or -alkenoic acid or (2) the hydrolysisof a 2-halo-3-phenylbenzofuran alkane cyanide followed by the selectivedisplacement of the 2-halogen atom of the intermediate by a nitro group,

C. the acid hydrolysis of the corresponding 2-nitro-3-phenylbenzofuranalkane or -alkene cyanide or of the corresponding2-nitro-3-phenylbenzofuranalkanoic or -alkenoic ester, and

D. the reduction of a cyano-3-phenylbenzofuran to the3-phenylbenzofuranaldehyde followed by halogenation and nitration ordirect nitration of the latter to form the2-nitro-3-phenylbenzofuranaldehyde, reacting that product with aceticanhydride to form the 2-nitro-3-phenylbenzofuranacrylic acid and, ifdesired, reducing the double bond in the side chain by means of chemicalhydrogenation to form the 2-nitro-3-phenylbenzofuranpropionic acid.

The direct nitration process (process A) can be carried out with fumingnitric acid in acetic acid or acetic anhydride or with dinitrogentetroxide in an inert solvent such as dichloromethane. In order to avoidnitration moderate temperatures of 0° to 30° C. are generally used.

The halogenation step of process B.(1) may be bromination or iodination.The bromination can be carried out using bromine water,N-bromosuccinimide or preferably bromine in a suitable solvent such asdichloromethane or acetic acid. Bromination is carried out under mildconditions, e.g. 0° to 30° C. to avoid aromatic bromination. The bromocompound may be isolated or used without isolation. Isolation may becarried out by extraction, precipitation by the addition of a solventsuch as water, evaporation of volatile reaction components, etc. Theiodination is carried out e.g. with molecular iodine in the presence ofyellow mercuric oxide in an inert solvent such as benzene. Generallythese reactions are carried out at about 25° to 125° C., for example atthe reflux temperature of the solvent.

Hydrolysis of 2-halo-3-phenylbenzofuranalkane cyanides of process B.(2)is effected under strongly acidic or basic conditions, for example inaqueous sulfuric acid at 60° C. to reflux or in aqueous alcoholic alkaliat its reflux temperature.

In the final step of process B, the 2-halo substituent can be displacedby means of selecting nitrating agents, such as strong nitric acidsolution, for example 70 percent aqueous nitric acid, dinitrogentetroxide in e.g. acetic acid or dichloromethane solution or a mixtureof sodium nitrite and a strong acid. When 70 percent nitric acid is usedas the nitrating reagent for 2-halo derivatives, preferably about two tothree moles each of sodium nitrite and nitric acid per mole ofbenzofuran is included. About four to twenty milliliters of acetic acidper gram of 2-halobenzofuran derivative is used, depending on itssolubility. It is desired to maintain the dissolution of the2-halobenzofuran derivative, and the amount of acetic acid and thereaction temperature are adjusted to achieve this result readily. Thereaction temperature is about 25° to 100° C., and preferably about 60°to 80° C. when the halogen is bromine.

It has been found that a mixture of sodium nitrite, sulfuric acid andacetic acid will also nitrate the 2-halobenzofuran derivativessuccessfully in the 2-position. The 2-halobenzofuran derivative isdissolved in acetic acid to maintain solution (up to 20 ml. per gramrequired) and concentrated sulfuric acid is added, from two to tenmilliliters per gram of benzofuran. Sodium nitrite is then added to thesolution. From two to five moles of nitrite per mole of benzofuranderivative is used. The reaction temperature is about 20° to 100° C.,and preferably about 55° C. The sodium nitrite can be replaced in thisreaction by other metal nitrites such as potassium nitrite.

A combination of nitrogen tetroxide in an inert solvent in the presenceof an alkene is one presently preferred nitration method according toprocess B, with acetic acid and dichloromethane as the preferredsolvents. For example, two to five liters of acetic acid per mole ofbenzofuran or halobenzofuran derivative are generally used. At least onemole of nitrogen tetroxide per mole of benzofuran is used. The exactamount depends on the rate of reaction desired, the extent ofvolatilization and other physical losses and the amount of competitiveaddition to the added olefin. An alkene is preferably used with a2-bromobenzofuran intermediate to remove the elements of BrNO₂ andminimize bromination as a side reaction. Cyclohexene is satisfactory forthis use. Preferably equimolar amounts of alkene and nitrogen tetroxideare used. The olefin is chosen to be less reactive to N₂ O₄ than thebenzofuran but more reactive to BrNO₂ than the benzofuran. An acidicolefin, e.g. 3-cyclohexene carboxylic acid is advantageous when thenitrated product is neutral. The temperature of these reactions isgenerally about 0° to 80° C., preferably 20° to 45° C. for bromineexchange and about 0° to 25° C. for iodine exchange and directnitration. When 2-iodobenzofurans are used, the olefin is not required(since the iodine is generally unreactive to the benzofuran under thereaction conditions) and only one-half mole of N₂ O₄ is theoreticallythen required.

The 2-nitro-3-phenylbenzofuranalkanoic and -alkenoic acid esters for usein process C are prepared by nitration of 2-unsubstituted or2-halo-phenylbenzofuranalkanoic and -alkenoic esters. These esters,preferably lower alkyl esters, are readily hydrolyzed by conventionalacid hydrolysis.

The novel 2-nitro-3-phenylbenzofuranalkane cyanides for use in process Care prepared (a) from novel bromomethyl-2-nitro-3-phenylbenzofurans bydisplacement of bromine with cyanide in inert solvents such as ketones,alcohols and N,N-dimethylformamide, generally at the reflux temperatureof the solvent or at about 100° C. or (b) by displacement of halogenfrom 2-bromo-3-phenylbenzofuranalkane cyanides using techniques andconditions described hereinabove. Hydrolysis of2-nitro-3-phenylbenzofuranalkane cyanides is effected under stronglyacidic or basic conditions, for example in aqueous sulfuric acid at 60°C. to reflux.

The aldehydes which are intermediates in process D are novel compoundsof the formula ##STR2## wherein X is halogen, lower alkyl, lower alkoxy,nitro, phenyl, cyano or trifluoromethyl, n is zero, one or two, and Y ismethyl, methoxy, halogen or hydrogen, and Q is hydrogen, bromine, iodineor nitro are novel and form an additional part of this invention. Thesenovel intermediates are prepared, for example, fromcyano-3-phenylbenzofurans which are known and are prepared by knownmethods. Preparation is carried out by reaction with aqueous formic acidin the presence of Raney nickel alloy at moderate temperatures, e.g. 50°to 125° C.

The novel 3-phenylbenzofurancarboxaldehydes may be 2-halogenated usingthe methods of this invention, optionally followed by displacement witha nitro group using the methods of this invention. The novel aldehydesof the invention are also readily converted directly to alkanoic andalkenoic acids of the invention. Condensation of2-nitro-3-phenylbenzofuranaldehydes with acetic anhydride in thepresence of sodium acetate provides a route to2-nitro-3-phenylbenzofuranacrylic acids, which acids can be reduced tothe corresponding propionic acids if desired using chemicalhydrogenation.

The pharmaceutically acceptable salts of the invention are readilyprepared by reaction of the corresponding free acids with theappropriate base and optionally in a suitable solvent and evaporation todryness. The base used to prepare the salts may be organic, e.g. sodiummethoxide or an amine, or inorganic. Furthermore, other salts which arenot pharmaceutically acceptable may be useful for the synthesis of theacid compounds or other acceptable salts or other useful intermediatessuch as esters. The acyl halides of the invention are prepared byreaction of the free acid with thionyl chloride, generally in anon-reactive solvent such as dichloromethane or benzene. The esters ofthe invention are prepared as described above in connection with theiruse in process C. The amides are generally prepared by reaction of theacyl halides (especially acyl chlorides) of the free acids of theinvention with the desired amines. The free acids can also be preparedfrom the corresponding esters, amides and acyl halides by methods knownto those skilled in the art.

The antimicrobial activity of the compounds is evaluated using avariation of the original agar-plate diffusion method of Vincent andVincent (e.g. see Vincent, J. G., and Vincent, Helen W., Proc. Soc.Exptl, Biol. Med. 55:162-164, 1944, and Davis, B. D., and Mingioli, E.S., J. Bac. 66:129-136, 1953. Using this test, the compounds of theinvention have been found to have a broad spectrum of activity againstboth gram-positive and gram-negative microorganisms. The procedureprovides information on the amount of a compound required to givecomplete inhibition, partial inhibition or no inhibition of microbialgrowth on agar plates. The microbial growth on each plate is readvisually, and minimal inhibitory concentrations are recorded.

The microorganisms used are:

1. Staphylococcus aureus

2. Bacillus subtilus

3. Pseudomonas aeruginosa

4. Escherichi coli

5. Streptococcus sp. .sup.(1)

6. Aspergillus niger

7. Candida albicans

8. Mima polymorpha

9. Herellea vaginicola

10. Klebsiella pneumoniae

11. Streptococcus fecaelis

These are selected representatives of various bacterial and fungalclasses, and broad spectrum activity can be predicted as a result ofactivity against them. All of the compounds of the invention possessantimicrobial activity towards one or more of the above microorganisms.The compounds maintain high activity against the microorganisms eitherin the absence or presence of ten percent horse serum.

The in vivo antimicrobial activity is determined against infectionsproduced by Streptococcus pyogenes C-203 and Staphylococcus aureus(Smith) or other bacterial species. The species used is determined bythe in vitro antimicrobial spectrum of the compound. Groups of five orten mice, 18-22 g., are infected intraperitoneally with the testculture. Treatment consists of three oral injections one, six andtwenty-four hours after infection. All mice are observed for extendedperiods, e.g. for two weeks, and deaths are recorded at daily intervals.Control groups consist of one infected, non-treated group and otherinfected groups receiving varying dosages of the reference standard.

The acute oral toxicity of the compounds of the invention generally ismoderate to low compared with the effective oral dose, and they have agood to excellent therapeutic ratio.

The compounds of the invention may be formulated by incorporating theminto conventional pharmaceutical carrier materials, either organic orinorganic, which are suitable for oral or intraperitoneal application.For in vitro or topical use, simple aqueous solutions or suspensions aremost conveniently employed. For this purpose, concentrations of theorder of 100 parts per million up to about five parts per thousand aresuitable, and the formulation is used by immersing the object to betreated therein, or by local application to an infected area. The amountof compound to be used for e.g. oral treatment of a microbial infectionwill be an effective amount less than a toxic amount. The amount to beadministered to a subject and route of administration to control aninfection will depend on the species of organism, the sex, weight,physical condition of the patient, the locus of the infection and manyother factors, but this judgment is well within the skill of the art.Usually the amount will be less than 100 mg/kg per dose. Convenientlythe oral treatment is administered in the form of the usualpharmaceutical preparation such as capsules, tablets, emulsions,solutions, suppositories and the like. Excipients, fillers, coatings,etc. are employed with tablets or capsules, as is well known in the art.

It is often advantageous to combine the compounds of this invention withother antimicrobial compounds such as coccidiostats, anthelmintics,antifungals, antibiotics, steroids or antibacterial agents, or tocombine more than one compound described herein in a single composition.

Certain of the compounds are also active antiparasitics as shown byactivity in laboratory tests versus the protozoan Trichomonas sp. Inview of the outstanding antimicrobial activity of the compounds, theywould also be expected to be effective growth promoters in variousanimal and bird species.

The following examples are given for the purpose of further illustratingthe procedures of the present invention, but are not intended, in anyway, to be limiting on the scope thereof. Thus, while the majority ofthe examples relate to the free acid compounds, the other compounds ofthe invention can also be prepared. The melting points are uncorrected,the temperatures are in degrees Centigrade and the pressures inmillimeters of mercury.

EXAMPLE 1

A prepared mixture of 15 ml. of acetic acid and 10 ml. of yellow fumingnitric acid is cooled to about 10° C. in an ice bath, and 4.8 g. (0.019mole) of 3-phenyl-6-benzofuranacetic acid (shown at column 18, line 1,of U.S. Pat. No. 3,862,134) is added with stirring. This mixture isstirred at room temperature for about one hour and then poured onto ice.A yellow solid precipitate which forms is extracted into diethyl ether.The ether solution is washed with saturated sodium chloride solution,with water, and then with the sodium chloride solution again. Thesolution is dried over sodium sulfate, and the ether is removed byevaporation under vacuum. The residue is a yellow solid which isrecrystallized twice from a mixture of ethanol and water, then from amixture of benzene and hexane to provide a yellow powder. This productis 2-nitro-3-phenyl-6-benzofuranacetic acid, m.p. 187°-191° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.11 NO.sub.5 :                                                     64.7     3.73     4.7                                       Found:            64.3     3.60     4.7                                       ______________________________________                                    

EXAMPLE 2

To a solution of 14.0 g. (0.055 mole) of 3-phenyl-7-benzofuranaceticacid (shown at column 17, line 63, of U.S. Pat. No. 3,862,134) in 150ml. of acetic acid is added 8.9 g. (0.055 mole) of bromine dropwise withstirring. After about one hour a precipitate begins to appear, and themixture is heated to 45° C. to maintain solution of the product which is2-bromo-3-phenyl-7-benzofuranacetic acid. Rather than isolating thisproduct, it is used as is. A solution of 7 ml. of concentrated sulfuricacid in 50 ml. of acetic acid is added to the reaction mixture. Next,13.8 g. (0.2 mole) of solid sodium nitrite is added in small portionsover a period of eight minutes while maintaining the reactiontemperature at about 55° C. The mixture is heated at 55° C. for abouttwo hours and is then poured into ice water. The precipitate which formsis extracted into diethyl ether, which is washed with water and sodiumchloride solution. The ether extracts are then dried over sodiumsulfate, filtered to remove the sodium sulfate, and evaporated todryness under vacuum. The residue is crystallized by suspending in asmall amount of diisopropyl ether. The product precipitate is a solidwhich is recrystallized twice from benzene, then twice from ethanol. Theyellow product is 2-nitro-3-phenyl-7-benzofuranacetic acid, m.p.170°-173° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.11 NO.sub.5 :                                                     64.7     3.7      4.7                                       Found:            64.5     3.6      4.6                                       ______________________________________                                    

EXAMPLE 3

To a mixture of 5.4 g. (0.02 mole) of3-(4-fluorophenyl)-7-benzofuranacetic acid (shown in Example 9 of U.S.Pat. No. 3,862,134) in 150 ml. of chloroform (stabilized with ethanol)is added dropwise 3.2 g. (0.02 mole) of bromine. The mixture is stirredfor about 16 hours, then evaporated. The residue is extracted withpetroleum ether, then the ether is evaporated to provide a white solid.The solid is recrystallized from hexane to provide ethyl2-bromo-3-(4-fluorophenyl)-7-benzofuranacetate, m.p. 63°-67° C.

To a solution of 3.8 g. (0.0101 mole) of ethyl2-bromo-3-(4-fluorophenyl)-7-benzofuranacetate in 30 ml. of acetic acidis added 2 ml. of 70 percent nitric acid and then 4 g. (0.0202 mole) ofsolid sodium nitrite in small portions over about 11/2 minutes. Themixture is stirred while heating gradually over 11/4 hours to about 80°C., allowed to cool, and poured into water. The ether extracts arewashed with water and twice with saturated sodium chloride solution. Theether extracts are then dried over sodium sulfate, filtered to removethe sodium sulfate and evaporated under vacuum to provide an orangeresidue. The product is separated from this residue by chromatography onneutral alumina. Elution is carried out by using a one to one mixture ofhexane and benzene followed by two portions of benzene. The desiredproduct elutes rapidly and is completely eluted by the benzene. Thefractions eluted by benzene are recrystallized from carbontetrachloride. The product is a white solid, ethyl 3-(4-fluorophenyl)-2-nitro-7-benzofuranacetate, m.p. 103°-104.5° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.18 H.sub.14 FNO.sub.5 :                                                    63.0     4.1      4.1                                       Found:            62.6     4.0      4.0                                       ______________________________________                                    

EXAMPLE 4

In 200 ml. of glyme are placed 28.6 g. (0.159 mole) of ethyl(4-hydroxyphenyl)acetate, 37.2 g. (0.159 mole) of4-chloro-α-bromoacetophenone and 28.6 g. of potassium carbonate. Themixture is heated at its reflux temperature for five hours, then dilutedwith water and diethyl ether. The ether layer is washed with water, cold0.5N sodium hydroxide solution and saturated sodium chloride solutionand treated with decolorizing charcoal, then dried. The solution isevaporated to provide a residue which is recrystallized from methanolyielding 24.4 g. of yellow crystals of condensation product, m.p.87°-92° C. This product is mixed with 165 g. of polyphosphoric acid andheated at 110° C. for 1.5 hours. The mixture is poured into ice andwater. This mixture is extracted with diethyl ether. The ether layer iswashed with water and saturated sodium chloride solution, then dried.Evaporation provides 20.7 g. of ethyl3-(4-chlorophenyl)-5-benzofuranacetate. This ester is hydrolyzed in 210ml. of ethanol with 21 ml. of water and 20.7 g. of sodium hydroxide byheating at reflux for two hours. The solution is evaporated, and theresidue is partitioned into water and diethyl ether. The water layer ispoured into cold dilute hydrochloric acid to provide a yellow, gummysolid. The solid is dissolved in diethyl ether. The ether layer iswashed with water and saturated sodium chloride solution, then dried.Evaporation provides a solid which is recrystallized twice from aqueousethanol, then from benzene to yield3-(4-chlorophenyl)-5-benzofuranacetic acid, m.p. 136°-140° C.

    ______________________________________                                         Analysis:         % C        % H                                             ______________________________________                                        Calculated for C.sub.16 H.sub.11 ClO.sub.3 :                                                     67.0       3.87                                            Found:             67.3       3.70                                            ______________________________________                                    

To a solution of 3-(4-chlorophenyl)-5-benzofuranacetic acid (9.7 g.,0.034 mole) in 100 ml. of chloroform is added dropwise with stirring asolution of 5.4 g. (0.034 mole) of bromine in 15 ml. of chloroformdropwise over one-half hour. Stirring is continued for an additional twohours. The reaction mixture is then evaporated under vacuum to provide2-bromo-3-(4-chlorophenyl)-5-benzofuranacetic acid, a green solid, m.p.152°-165° C.

The 2-bromo compound is mixed without further purification with 106 ml.of acetic acid, and the mixture is warmed until solution is obtained.The mixture is allowed to cool to room temperature, then 56 ml. of 70percent nitric acid are added. To this mixture is added sodium nitrite(4.7 g., 0.068 mole) in small portions. The mixture is heated at 80° C.over a period of one hour. The mixture is then poured into cold water.The yellow solid product is separated by filtration and washed withwater. After three recrystallizations from 95 percent ethanol theproduct, 3-(4-chlorophenyl)-2-nitro-5-benzofuranacetic acid, is a yellowpowder, m.p. 211° C. (dec.).

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.10 ClNO.sub.5 :                                                   57.9     3.04     4.22                                      Found:            58.3     3.00     3.80                                      ______________________________________                                    

EXAMPLE 5

To a solution of 3.85 g. (0.0775 mole) of sodium hydride in 150 ml. ofglyme is added 18 g. (0.0775 mole) of 7-cyanomethyl-3-phenylbenzofuran(shown at column 17, line 31, of U.S. Pat. No. 3,862,134), and themixture is heated to its reflux temperature and maintained at reflux forabout one hour. The solution is then cooled with an ice bath and 33 g.(0.23 mole) of methyl iodide is added slowly. The reaction mixture isstirred for about sixteen hours at about 21° C. To the mixture is addeda few milliliters of ethanol, then it is evaporated to dryness. Diethylether and water are added and mixed thoroughly. The ether layer iswashed with saturated sodium chloride solution, dried, then evaporatedto provide an oil.

This oil is dissolved in 200 ml. of ethanol, 40 g. of potassiumhydroxide are added, and the mixture is heated at its reflux temperaturefor about sixteen hours. The mixture is partially evaporated, and theconcentrate is extracted with a mixture of diethyl ether and hexane. Theorganic fraction is evaporated to provide an oil. The oil is extractedwith hexane. The extracts are evaporated to provide a residue which isfurther hydrolyzed by dissolving it in 100 ml. of ethylene glycol with10 g. of 85 percent potassium hydroxide and heating the mixture at 130°C. for sixteen hours. The product is isolated by evaporating to providea residue, extracting the residue with diethyl ether and hexane andacidifying the aqueous layer to give a white solid which is dissolved indiethyl ether. The ether layer is washed with water, dried, thenevaporated. The residue is recrystallized from a benzene-hexane mixture,then from aqueous ethanol to provide off-white crystals ofα,α-dimethyl-3-phenyl-7-benzofuranacetic acid, m.p. 169°-171° C.

    ______________________________________                                         Analysis:         % C        % H                                             ______________________________________                                        Calculated for C.sub.18 H.sub.16 O.sub.3 :                                                       77.1       5.75                                            Found:             76.8       5.50                                            ______________________________________                                    

Bromination of this compound using the method of Example 4 provides2-bromo-α,α-dimethyl-3-phenyl-7-benzofuranacetic acid, m.p. 183°-196° C.Further reaction of this intermediate product, also using the method ofExample 4, provides α,α-dimethyl-2-nitro-3-phenyl-7-benzofuranaceticacid, m.p. 256.5°-258.5° C. The compounds of Examples 6-8, shown inTable I, are also prepared according to the method of Example 4. Thestarting materials therefor are shown in U.S. Pat. No. 3,862,134,respectively at column 18, lines 12-13, in Example 5, and in Example 9.In cases where the intermediate 2-bromo compound has been isolated, themelting point is given.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                             Intermediate Bromo                                                                            Final         Melting Point                             No.   Compound        Product       (° C).                             __________________________________________________________________________    6     2-bromo-3-(4-chlorophenyl)-7-                                                                 3-(4-chlorophenyl)-2-                                                                       233-235                                         benzofuranacetic acid                                                                         nitro-7-benzofuran-                                                           acetic acid                                             7     2-bromo-α-methyl-3-phenyl-7-                                                            α-methyl-2-nitro-3-phenyl-                                                            178-180                                         benzofuranacetic acid, m.p.                                                                   7-benzofuranacetic acid                                       153.5-155.5° C.                                                  8     2-bromo-3-(4-fluorophenyl)-7-                                                                 3-(4-fluorophenyl)-2-nitro-                                                                   191-194.5                                     benzofuranacetic acid, m.p.                                                                   7-benzofuranacetic acid                                       169-170° C.                                                      __________________________________________________________________________

EXAMPLE 9

To a stirred solution of 18.2 g. (0.72 mole) of3-phenyl-5-benzofuranacetic acid (shown at column 17, line 65, of U.S.Pat. No. 3,862,134) in 400 ml. of dichloromethane is added 8.2 g. (0.10mole) of sodium acetate and then, dropwise, a solution of 11.5 g. (0.072mole) of bromine in 25 ml. of dichloromethane. After one hour theaddition of the diluted bromine is stopped with 3.2 ml. of solutionremaining. The solution is allowed to stir for about 11/2 hoursadditional. The reaction mixture is washed with water, with 10 percentaqueous sodium bisulfite, then again with water. The dichloromethanefraction is then dried over magnesium sulfate and filtered to remove themagnesium sulfate. The resulting solution is concentrated under vacuumto provide 2-bromo-3-phenyl-5-benzofuranacetic acid, a white powder,m.p. 130°-140° C. This solid is used without further purification. Amixture of 23.8 g. (0.072 mole) of 2-bromo-3 -phenyl-5-benzofuranaceticacid in 250 ml. of acetic acid is warmed to achieve solution, thenallowed to cool to room temperature. To this solution is added 8.9 g.(0.108 mole) of cyclohexene and then, dropwise, a solution of 9.9 g.(0.108 mole) of dinitrogen tetroxide in 25 ml. of acetic acid. After thesolution has stirred for a period of three hours, the precipitate whichhas formed is collected by filtration, washed with cold acetic acid,with water and finally with petroleum ether. The yellow-green solidproduct is recrystallized twice from 95 percent ethanol and once fromisopropyl alcohol to provide a yellow crystalline solid,2-nitro-3-phenyl-5-benzofuranacetic acid, m.p. 209°-212° C.

    ______________________________________                                         Analysis:        % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.11 NO.sub.5 :                                                     64.6     3.7      4.7                                       Found:            64.3     4.0      4.5                                       ______________________________________                                    

EXAMPLE 10

A solution of 2 g. of 2-nitro-3-phenyl-5-benzofuranacetyl chloride(shown in the first paragraph of Example 30 hereof) in 75 ml. of benzeneis treated with gaseous ammonia. A precipitate forms rapidly and isseparated by filtration. Recrystallization from 95 percent ethanolprovides yellow solid 2-nitro-3-phenyl-5-benzofuranacetamide, m.p.220.5°-222.5° C.

The compounds of the following table, which are representative of theamino sugar amides, dialkylaminoalkyl amides, amino acid amides andalkylsulfonamides of the present invention, are prepared using thesynthetic method described in Example 10 starting with2-nitro-3-phenyl-5-benzofuranacetyl chloride and the appropriate knownamine or amide salt.

                                      TABLE II                                    __________________________________________________________________________    Product                      Melting Point (° C)                       __________________________________________________________________________     ##STR3##                    206-207 (dec.)                                    ##STR4##                    183-185                                           ##STR5##                    159.5-161.5                                       ##STR6##                    199-201                                           ##STR7##                    219.5-221.5                                      __________________________________________________________________________

example 11

to a solution of 16.1 g. (0.060 mole) of 3-phenyl-5-benzofuranpropionicacid (shown in Example 16 of U.S. Pat. No. 3,862,134) in 300 ml. ofdichloromethane is added sodium acetate (8.2 g., 0.10 mole), then asolution of bromine (9.6 g., 0.06 mole) in 25 ml. of dichloromethane.The mixture is stirred for a total of two hours, then washed with water,10 percent sodium bisulfite solution and water, and finally withsaturated sodium chloride solution. The dichloromethane fraction is thendried and concentrated to provide a tan solid,2-bromo-3-phenyl-5-benzofuranpropionic acid, crude m.p. 70°-80° C. Thisproduct is used without further purification for the next step.

To a solution of 2-bromo-3-phenyl-5-benzofuranpropionic acid (20.7 g.,0.060 mole) in 250 ml. of acetic acid is added 7.4 g. (0.090 mole) ofcyclohexane, then, dropwise, 8.3 g. (0.090 mole) of dinitrogen tetroxidein 25 ml. of acetic acid. After stirring a total of three hours themisture is poured into cold water, then extracted with eleven 100 ml.portions of cold 0.5N sodium hydroxide solution. Extracts 7 through 11are combined and poured into cold dilute hydrochloric acid. The crudeproduct is taken up in diethyl ether, the ether extracts are washed withwater and saturated sodium chloride solution, then dried andconcentrated to provide a tan residue. The product is purified bychromatography on 40 to 140 mesh silica gel (about 200 g.). The columnis eluted with chloroform containin 1 percent acetic acid. The first1050 ml. of eluate is evaporated to a yellow solid which isrecrystallized from 95 percent ethanol, then from benzene to provideyellow crystals of 2-nitro-3-phenyl-5-benzofuranpropionic acid, m.p.174°-178° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.13 NO.sub.5 :                                                     65.7     4.2      4.5                                       Found:            65.7     4.1      4.5                                       ______________________________________                                    

EXAMPLE 12

Using the method of Example 11, 3-phenyl-7-benzofuranpropionic acid(i.e. 3-[7-(3-phenylbenzofuran)]propionic acid as shown in the secondparagraph of Example 12 of U.S. Pat. No. 3,862,134) is brominated toprovide 2-bromo-3-phenyl-7-benzofuranpropionic acid, m.p. 182°-183.5° C.

A mixture of 2-bromo-3-phenyl-7-benzofuranpropionic acid (7.0 g., 0.0203mole) and 400 ml. of acetic acid is warmed to effect solution.Cyclohexene (2.05 g., 0.025 mole) is added, followed by dropwiseaddition of dinitrogen tetroxide (2.3 g., 0.025 mole) in 10 ml. ofacetic acid. The solution is heated at 55° C. for about one-half hour.An additional 0.5 g. of dinitrogen tetroxide dissolved in 5 ml. ofacetic acid is added dropwise at this time, then the mixture is heatedat 55° C. for another hour. The mixture is then cooled and added to anice water mixture. The precipitate is separated by filtration. Theproduct is dissolved in dilute sodium hydroxide, and the solution istreated with decolorizing charcoal, and the product is precipitated withdilute hydrochloric acid. The precipitate is extracted into chloroform(about 2 liters) then the chloroform extracts are dried over magnesiumsulfate. The extracts are filtered to remove the magnesium sulfate andevaporated under vacuum. The residue is recrystallized twice fromethanol with concomitant treatment with decloroizing charcoal, thenrecrystallized once from methanol, again treating with decolorizingcharcoal. The product is a yellow solid,2-nitro-3-phenyl-7-benzofuranpropionic acid, m.p. 217.5°-219.5° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.13 NO.sub.5 :                                                     65.6     4.2      4.5                                       Found:            65.7     4.1      4.5                                       ______________________________________                                    

EXAMPLE 13

Pyridine (6.5 ml.), 10.3 g. (0.115 mole) of cuprous cyanide and 22.8 g.(0.1 mole) of 7-chloro-3-phenylbenzofuran (shown at column 14, line 30,of U.S. Pat. No. 3,862,134) are heated at 220° C. for about three hours,then at 150° to 190° C. for about 16 hours. The solution is added to 40g. of ferrous chloride hexahydrate in 65 ml. of water and 15 ml. ofconcentrated hydrochloric acid. The resulting mixture is heated withstirring at 90° C. for about one hour, then filtered hot. The filtrateis cooled, and the product separated by filtration. The product isheated in a boiling benzene-toluene mixture (200 ml/250 ml), then themixture is decanted. The decantate is evaporated to half of its volumeand separated from the dark, solid residue. The residues are againextracted with a boiling mixture of benzene-toluene (400 ml/200 ml), andthe combined organic extracts are washed with 125 ml. 6N hydrochloricacid, water, 10 percent sodium hydroxide and water. The extracts aredried, treated with decolorizing charcoal, then evaporated to providecrude 7-cyano-3-phenylbenzofuran which is recrystallized from a mixtureof benzene and petroleum ether. The white product has a m.p. 143°-145°C.

7-Cyano-3-phenylbenzofuran (45 g., 0.0206 mole) is dissolved in formicacid (580 ml plus 25 ml. water) at 85° C. At this temperature and undera nitrogen atmosphere, 30 g. of Raney nickel alloy is added. The mixtureis stirred for 45 minutes at this temperature. At this time anadditional 10 g. of Raney nickel is added, and two hours later anadditional 5 g. of Raney nickel is added. The mixture is cooled, mixedwith sulfur to inactivate the catalyst and filtered. The catalyst iswashed with dichloromethane. The filtrate is diluted with water anddichloromethane. The dichloromethane solution is washed with water twiceand then twice with saturated sodium bicarbonate solution and thenfinally again with water. The organic solution is then dried andconcentrated to provide a gray solid. This solid is3-phenyl-7-benzofurancarboxaldehyde. Its structural assignment isconfirmed by its infrared spectral characteristics.

A solution of 3-phenyl-7-benzofuranylaldehyde (20 g., 0.09 mole) in 300ml. of dichloromethane is cooled to 15° C., and bromine (14.4 g., 0.09mole) dissolved in 15 ml. of dichloromethane is added dropwise over 15minutes while stirring. After stirring for five minutes the reactionmixture is washed twice with saturated sodium bicarbonate solution,washed with water, and then dried over magnesium sulfate. Thedichloromethane solution is then filtered to remove the magnesiumsulfate and evaporated to dryness while maintaining the temperature ofthe mixture below 25° C. Benzene is then added, and the mixture is againevaporated under vacuum. The product is purified by columnchromatography on 210 g. of fluorisil. The product is dissolved in 40ml. of benzene and placed on a column with one liter of hexane-benzene(2:1). The product is eluted with 1:1 hexane-benzene and benzene.

The product from the preceding step,2-bromo-3-phenyl-7-benzofurancarboxaldehyde (29.5 g., 0.098 mole), isdissolved by warming in 150 ml. of acetic acid. The mixture is cooled to40° C. and 15.2 g. (0.12 mole) of cyclohexene is added, followed by adropwise addition of a solution of dinitrogen tetroxide (12.6 g., 0.14mole) dissolved in about 30 mo. of acetic acid. The mixture is heated atabout 55° C. for a total of three hours. It is then cooled to roomtemperature, and a yellow precipitate forms which is separated byfiltration. The precipitate is washed with acetic acid, then withdiethyl ether. The precipitate is dissolved in dichloromethane, and thedichloromethane solution is washed with water, with saturated sodiumcarbonate solution, then twice with water. The dichloromethane extractsare dried over magnesium sulfate, then filtered to remove the magnesiumsulfate and evaporated under vacuum to provide a yellow residue. Thissolid is the novel compound 2-nitro-3-phenyl-7-benzofuranaldehyde, m.p.169°-173° C. It is used without further purification for the next step.The pure aldehyde has m.p. 174°-176° C.

A mixture of 5.1 g. (0.0191 mole) of2-nitro-3-phenyl-7-benzofuranaldehyde, sodium acetate (2.3 g., 0.0278mole) and acetic anhydride (9.1 g.) is heated at 145°-150° C. withstirring. After 16 hours of heating, an additional 10 ml. of aceticanhydride is added and refluxing is continued for five additional hours.The mixture is stirred into 200 ml. of water, and the residue isseparated by filtration and washed with water. The residue is dissolvedin a solution of 30 ml. of concentrated ammonium hydroxide in 400 ml. ofwater, filtered, and added to 10 percent sulfuric acid solution. Anoff-yellow solid is obtained which is washed with water and then withdiethyl ether. The product is recrystallized twice from acetic acid,with treatment with decolorizing charcoal. The product is2-nitro-3-phenyl-7-benzofuranacrylic acid, m.p. 281.5°-283° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.11 NO.sub.5 :                                                     66.0     3.6      4.5                                       Found:            65.8     3.4      4.4                                       ______________________________________                                    

EXAMPLE 14

A mixture of 2.97 g. (10 moles) of 2-nitro-3-phenyl-5-benzofuranaceticacid (shown in Example 9 hereof) in 125 ml. of methanol is warmed toeffect complete solution, and 10 ml. of 1.0M sodium hydroxide solutionis added. The solvent is evaporated under vacuum, benzene is added, andthe mixture is again evaporated under vacuum to provide a solid residue.The crystalline residue is recrystallized from a mixture of ethanol andpetroleum ether to provide a light yellow product which is washed withpetroleum ether. A second recrystallization provides sodium2-nitro-3-phenyl-5-benzofuranacetate, m.p. 270°-273° C. (dec.).

    ______________________________________                                        Analysis:           % C      % H    % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.10 NNaO.sub.5 :                                                     58.9     3.10   4.30                                      Found:              58.5     3.35   4.26                                      ______________________________________                                    

EXAMPLE 15

A mixture of 2-nitro-3-phenyl-5-benzofuranacetic acid (3.0 g., 0.010mole), thionyl chloride (1.8 g., 0.015 mole) and 200 ml. ofdichloromethane is heated to its reflux temperature and maintained atreflux for about five hours. The mixture is evaporated under vacuum toprovide a residue, benzene is added to the residue, and the mixture isagain evaporated under vacuum to dryness. This is repeated three moretimes. The residue is a yellow oil which is analyzed by infraredspectroscopy to confirm that it is 2-nitro-3-phenyl-5-benzofuranacetylchloride.

EXAMPLE 16

A mixture of 2-nitro-3-phenyl-7-benzofuranacetic acid (2.6 g.), sulfuricacid (2.6 g.) and ethanol (25 ml.) is heated to its reflux temperatureand maintained at reflux for about 16 hours. The mixture is added to 200ml. of ice water and extracted with diethyl ether, and the etherextracts are washed with water, then three times with saturated sodiumbicarbonate solution, then again with water and finally twice withsaturated sodium chloride solution. The ether solution is dried overmagnesium sulfate, then filtered to remove the magnesium sulfate andevaporated under vacuum. The residue is a yellow solid which isrecrystallized from cyclohexane in the presence of decolorizingcharcoal. The product is ethyl 2-nitro-3-phenyl-7-benzofuranacetate,m.p. 87°-88° C.

    ______________________________________                                         Analysis:        % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.18 H.sub.15 NO.sub.5 :                                                     66.45    4.6      4.3                                       Found:            66.50    4.5      4.3                                       ______________________________________                                    

EXAMPLE 17

Equimolar amounts of 3-hydroxytoluene and α-bromoacetophenone arerefluxed in benzene in the presence of potassium carbonate to provideα-(3-methylphenoxy)acetophenone.

A mixture of four parts by weight polyphosphoric acid to one partα-(3-methylphenoxy)acetophenone is heated at about 125° C. for severalhours, then poured into an ice-water mixture. The solid product isolatedby filtration is a mixture of (about 2:3) 4-methyl-3-phenylbenzofuranand 6-methyl-3-phenylbenzofuran. This mixture is treated with liquidbromine in dichloromethane to provide a mixture of2-bromo-4-methyl-3-phenylbenzofuran and2-bromo-6-methyl-3-phenylbenzofuran which is fractionallyrecrystallized. One fraction contains a 1:3 ratio of the 6 isomer to the4 isomer. This fraction is chromatographed on a silica gel column,eluting with large volumes of petroleum ether to provide early fractionsof about 85 percent 4-methyl isomer.

A mixture of 2-bromo-4-methyl-3-phenylbenzofuran and2-bromo-6-methyl-3-phenylbenzofuran (about 15 percent 6 isomer) (51.5g., 0.179 mole), N-bromosuccinimide (37.7 g., 0.178 mole) and benzoylperoxide (about 0.05 g.) in 400 ml. of carbon tetrachloride is heated atits reflux temperature while shining a sunlamp on the mixture untilreaction is complete. The mixture is cooled, then filtered to removesuccinimide, and the organic layer is evaporated to dryness andsuspended in petroleum ether. The white solid product is separated byfiltration. It is about 95 percent pure2-bromo-4-bromomethyl-3-phenylbenzofuran. The2-bromo-4-bromomethyl-3-phenylbenzofuran (44.5 g., 0.122 mole) dissolvedin acetone (165 ml.), aqueous (30 ml.) sodium cyanide (6.0 g., 0.122mole) and ethanol (112 ml.) are mixed and heated to reflux. After aboutfive hours of heating the mixture is allowed to stir at about 25° C. forabout 16 hours. The reaction mixture is evaporated under vacuum, theresidue is dissolved in diethyl ether and water-washed, and the organiclayer is again concentrated to provide an oily brown solid,2-bromo-4-cyanomethyl-3-phenylbenzofuran.

A solution of 37 g. of 2-bromo-4-cyanomethyl-3-phenylbenzofuran in 235ml. of absolute ethanol is treated with 15 g. of potassium hydroxide in15 ml. of water, and the mixture is refluxed for about two days. Themixture is concentrated by evaporation, water is added, and the mixtureis extracted with diethyl ether. The water layer is acidified withhydrochloric acid, then this mixture is extracted with dichloromethane.The extracts are dried, then evaporated under vacuum to provide a brownresidue. The residue is treated with diethyl ether and a solid formswhich is separated by filtration and washed with isopropyl alcohol. Theproduct is 2-bromo-3-phenyl-4-benzofuranacetic acid, m.p. 131°-133° C.

    ______________________________________                                        Analysis:             % C      % H                                            ______________________________________                                        Calculated for C.sub.16 H.sub.11 BrO.sub.3 :                                                        58.05    3.35                                           Found:                58.10    3.40                                           ______________________________________                                    

A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365mole) and cyclohexane (3.3 g., 0.04 mole) in 100 ml. of chloroform istreated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroformdropwise. The mixture is stirred for 16 hours at about 25° C. then at50°-55° C. for about 20 minutes. The mixture is washed with water, andthe organic layer is treated with an aqueous base. The aqueous layer isacidified, then extracted with dichloromethane. The organic layer iswashed thrice with water, dried and evaporated. Two recrystallizationsfrom benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranaceticacid, m.p. 187.5°-189.5° C.

EXAMPLE 18

Using the method of Example 17 and starting with 2,4-dimethylphenol andα-bromoacetophenone and cyclizing at 50°-60° C.,5,7-dimethyl-3-phenylbenzofuran is obtained.

To a solution of 5 g. (0.0225 mole) of 5,7-dimethyl-3-phenylbenzofuranin 30 ml. of carbon tetrachloride and 8.0 g. (0.045 mole) ofN-bromosuccinimide in 30 ml. of carbon tetrachloride is added 0.01 g. ofbenzoyl peroxide. The mixture is heated to its reflux temperature whileirradiating with a sunlamp and maintained at reflux for about 30minutes, cooled and filtered. The filtrate is evaporated to an oilyresidue. The residue is about two-thirds of the desired2-bromo-5-bromomethyl-7-methyl-3-phenylbenzofuran according to nuclearmagnetic resonance spectral analysis. This mixture is dissolved inacetone (34 ml.), and sodium cyanide (1.3 g.) in 6 ml. of ether isadded. The mixture is added to 25 ml. of ethanol, heated to its refluxtemperature and maintained at reflux for about 40 hours. The mixture isevaporated, the residue is treated with water and diethyl ether, and theresulting ether layer is separated, dried and evaporated. The brown oilresidue is purified on a silica gel column to provide 3.9 g. of a yellowoil which is chiefly 2-bromo-5-cyanomethyl-7-methyl-3-phenylbenzofuran.

To a solution of the 2-bromo-5-cyanomethyl-7-methyl-3-phenylbenzofuranin 80 ml. of aqueous ethanol is added 4 g. of potassium hydroxide, andthe mixture is heated at its reflux temperature for about 65 hours. Thesolvent is removed by evaporation, the residue is mixed into water, andthe mixture is extracted with dichloromethane. The aqueous layer isacidified, then extracted with diethyl ether. The extracts are washedwith water and saturated sodium chloride solution, dried and evaporated.The residue is recrystallized from benzene and a little hexane to give0.89 g. of white solid 2-bromo-7-methyl-3-phenyl-5-benzofuranaceticacid, m.p. 183.5°-189° C. A solution of2-bromo-7-methyl-3-phenyl-5-benzofuranacetic acid (0.89 g., 0.0027 mole)in 50 ml. of chloroform, 0.43 g. of cyclohexene and 0.57 g. ofdinitrogen tetroxide is stirred for about 16 hours. The mixture iswashed with water, extracted with saturated sodium bicarbonate solution,and the aqueous extracts are acidified. The solution is extracted withdichloromethane, and the extracts are dried and evaporated. The solidresidue is recrystallized twice from 4:1 benzene:hexane to provideyellow solid 7-methyl-2-nitro-3-phenyl-5-benzofuranacetic acid m.p.189°-191.5° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.13 NO.sub.5 :                                                     65.6     4.2      4.5                                       Found:            65.5     4.2      4.3                                       ______________________________________                                    

EXAMPLE 19

Using the method of Example 17 and starting with 4-hydroxytoluene andα-bromoacetophenone one obtains α-(4-methylphenoxy)acetophenone.

Using the method of Example 17 α-(4-methylphenoxy)-acetophenone iscyclized with polyphosphoric acid at 60° C. to provide5-methyl-3-phenylbenzofuran, m.p. 144.5°-146° C.

A solution of 5-methyl-3-phenylbenzofuran (112 g., 0.538 mole) dissolvedin 500 ml. of carbon tetrachloride is treated with 192 g. (1.076 mole)of N-bromosuccinimide. Benzoyl peroxide (0.1 g.) is added, and themixture is stirred and heated to its reflux temperature whileirradiating with a sunlamp. After about one hour, 0.5 g. of t-butylhydroperoxide and 0.5 g. of cobalt stearate are added. The mixture isrefluxed for about two hours, then allowed to come to room temperature.The mixture is filtered, and the filtrate is concentrated under vacuumto provide an oily yellow solid. The solid is washed with petroleumether with scratching, and the precipitate is collected and dried. Thecrude product is 2-bromo-5-bromomethyl-3-phenylbenzofuran, m.p. 99°-108°C. The structural assignment is confirmed by infrared and nuclearmagnetic resonance spectral analysis.

A solution of 2-bromo-5-bromomethyl-3-phenylbenzofuran (49.4 g., 0.135mole) in 1100 ml. of acetic acid is warmed to 55° C. with 25.4 g. (0.202mole) of cyclohexene-4-carboxylic acid. To this solution is addeddropwise 18.6 g. (0.202 mole) of dinitrogen tetroxide in 40 ml. ofacetic acid over about two hours. The precipitated product is collectedby filtration, washed with cold acetic acid, water and petroleum ether.The yellow crystals of novel product,5-bromomethyl-2-nitro-3-phenylbenzofuran, are dried to m.p. 172°-180° C.

A solution of 5-bromomethyl-2-nitro-3-phenylbenzofuran (5 g., 0.015mole) in 95 ml. of acetone is treated with 20 ml. of ethanol, and themixture is heated to its reflux temperature. To this mixture is added0.015 mole of sodium cyanide dissolved in 9 ml. of water, and refluxingis continued for about two hours. The mixture is evaporated undervacuum, then dichloromethane and water are added to the residue. Theorganic layer is separated, washed with water and dried. The organiclayer is then evaporated under vacuum. The residue is purified byeluting twice with benzene through a silica gel column, followed byrefluxing in 30 ml. of diethyl ether. The yellow precipitate isseparated by filtration and recrystallized twice from benzene to provide5-cyanomethyl-2-nitro-3-phenylbenzofuran, m.p. 166°-168° C.

A one ml. portion of 50 percent sulfuric acid is added to 0.1 g. of5-cyanomethyl-2-nitro-3-phenylbenzofuran, and the mixture is heatedslowly over one hour in an oil bath to about 160° C. bath temperature.The mixture is heated at this temperature for an additional 1.5 hours,allowed to cool, and poured into water. The aqueous mixture is extractedtwice with dichloromethane, the organic extracts are washed with water,dried, and evaporated under vacuum. The residue is a yellow solid,2-nitro-3-phenylbenzofuran-5-acetic acid. Its spectral characteristicsconfirm that it is the same as the product obtained in Example 9.

EXAMPLE 20

Step 1. A mixture of 50 g. (0.175 mole) of 4-phenyl-α-bromoacetophenone,30.6 g. (0.17 mole) of ethyl 4-hydroxyphenylacetate and 36 g. (0.26mole) of potassium carbonate in 500 ml. of benzene is heated to itsreflux and maintained at reflux for about 16 hours while removing waterthrough a Dean-Stark trap. The mixture is filtered, washed with waterand saturated sodium chloride solution and dried over calcium sulfate.Evaporation of the benzene provides a residue which is recrystallizedfrom a benzene-hexane mixture, then an ethylacetate-hexane mixture toprovide white plates of ethyl4-(4-phenylbenzoylmethoxy)phenylacetate.The structural assignment of the product is established by nuclearmagnetic resonance spectral analysis.

Step 2. A stirred mixture containing 15 g. of the product of Step 1 and150 g. of polyphosphoric acid is heated at about 130° C. for about 45minutes. The mixture is poured into one liter of water and stirred. Ayellow solid forms and is collected and recrystallized from a mixture ofethyl acetate and hexane to provide ethyl3-(4-biphenylyl)-5-benzofuranacetate. The structural assignment of theproduct is checked by nuclear magnetic resonance spectral analysis.

Step 3. A mixture of 6.5 g. of the ester product of Step 2, 150 ml. ofethanol and 150 ml. of ten percent sodium hydroxide solution is heatedon a steam cone. After about 1.5 hours most of the solid dissolves. Themixture is filtered hot, and the filtrate is cooled.

The mixture is heated on a steam cone for about 30 minutes, thenacidified with 6N hydrochloric acid. The solid product is3-(4-biphenylyl)-5-benzofuranacetic acid, m.p. 230°-233° C.

Step 4. A mixture of 1.5 g. (4.6 mmoles) of3-(4-biphenylyl)-5-benzofuranacetic acid in 250 ml. of dichloromethaneis treated with 0.5 g. (5 mmoles) of dinitrogen tetroxide, and themixture is stirred for about 16 hours. The mixture is evaporated todryness, and the residue is recrystallized from ethyl acetate to provideyellow crystals of 2-nitro-3-(4-biphenylyl)-5-benzofuranacetic acid,m.p. 230°-233° C.

    ______________________________________                                        Analysis:         % C      % H      % N                                       ______________________________________                                        Calculated for C.sub.22 H.sub.15 NO.sub.5 :                                                     70.8     4.1      3.7                                       Found:            70.7     4.1      3.7                                       ______________________________________                                    

EXAMPLE 21

Using the method of Example 20 and starting withα-bromo-3-methoxy-acetophenone and ethyl 4-hydroxyphenylacetate oneobtains 3-(3-methoxyphenyl)-2-nitro-5-benzofuranacetic acid.

    ______________________________________                                        Analysis:             % C     % H     % N                                     ______________________________________                                        Calculated for C.sub.17 H.sub.13 NO.sub.6 · 1/2H.sub.2 O:                                  60.7    4.2     4.2                                     Found:                60.7    3.8     4.4                                     ______________________________________                                    

EXAMPLE 22

Starting with 4-bromo-α-bromoacetophenone and 4-hydroxyphenylacetic acidand using the method of Example 2, Steps 1 and 2, one obtains ethyl3-(4-bromophenyl)-5-benzofuranacetate.

A mixture of 20 g. (0.056 mole) of ethyl3-(4-bromophenyl)-5-benzofuranacetate, 6.0 g. (0.067 mole) of cuprouscyanide and 5 ml. of pyridine is stirred under a nitrogen atmospherewhile heating with an oil bath at 150° to 160° C. for about 18 hours.The reaction mixture is then poured into a mixture of 18 g. of ferricchloride, 10 ml. of concentrated hydrochloric acid and 50 ml. of water.The mixture is heated on a steam cone for about 1.5 hours, extractedwith diethyl ether and the extracts washed with 6N hydrochloric acid, 10percent sodium hydroxide and saturated sodium chloride solution. Thedried solution is filtered, evaporated to about 25 ml., and hexane isadded. The product is collected, dissolved in diisopropyl ether andtreated with decolorizing charcoal. The filtrate is evaporated to 50ml., and the precipitate, ethyl 3-(4-cyanophenyl)-5-benzofuranacetate iscollected.

To a solution of 2.5 g. (8.2 mmoles) of the ester in 75 ml. of methanol,0.48 g. (8.2 mmoles) of 85 percent potassium hydroxide is added, and themixture is stirred for about 16 hours. The solution is diluted with 75ml. of water, the acidified with hydrochloric acid. The precipitate isseparated, dissolved in boiling chloroform and dried. Hexane is added tothe solution until the product, 3-(4-cyanophenyl)-5-benzofuranaceticacid, precipitates.

A solution of 1.0 g. of 3-(4-cyanophenyl)-5-benzofuranacetic acid and 1g. of dinitrogen tetroxide in 200 ml. of dichloromethane is stirred forabout 16 hours. Evaporation of the reaction mixture leaves a residuewhich is dissolved in chloroform. The solution is placed on a column of50 g. of silica gel for chromatography. Elution with chloroform providesthe desired product as a yellow crystalline solid,3-(4-cyanophenyl)-2-nitro-5-benzofuranacetic acid, m.p. 220°-222° C.

The compounds of the following table are prepared using the syntheticmethod described in Example 20, starting with 4-hydroxyphenylacetic acidand the appropriate known substituted α-bromoacetophenone.

    __________________________________________________________________________    Example                                                                            Starting                                  Melting Point                  Number                                                                             Material       Product                    (in ° C.)               __________________________________________________________________________    23                                                                                  ##STR8##                                                                                     ##STR9##                  200-203                        24                                                                                  ##STR10##                                                                                    ##STR11##                 181-184                        25                                                                                  ##STR12##                                                                                    ##STR13##                 190-193                        26                                                                                  ##STR14##                                                                                    ##STR15##                 239-241                        27                                                                                  ##STR16##                                                                                    ##STR17##                 139-141                        28                                                                                  ##STR18##                                                                                    ##STR19##                 230-233                        29                                                                                  ##STR20##                                                                                    ##STR21##                 204-206 (dec.)                 __________________________________________________________________________

EXAMPLE 30

Thionyl chloride is reacted with 2-nitro-3-phenylbenzofuran-5-aceticacid (shown in Example 9 hereof) to provide2-nitro-3-phenyl-5-benzofuranacetyl chloride.

A mixture of 3 g. of 2-nitro-3-phenyl-5-benzofuranacetyl chloride and 30ml. of ethylene glycol in 130 ml. of chloroform is heated to its refluxtemperature and maintained at reflux temperature for 3.5 hours. Themixture is then extracted thrice with water and washed with saturatedsodium bicarbonate solution, twice with water and once with saturatedsodium chloride solution. The organic layer is dried, then evaporated toprovide a residue which solidifies. Recrystallization from 1:1cyclohexane-benzene, then benzene and finally ethanol provides2-hydroxyethyl 2-nitro-3-phenyl-5-benzofuranacetate, m.p. 104°-107° C.

EXAMPLE 31

A mixture of 2.59 g. (8.2 mmoles) of 2-nitro-3-phenyl-5-benzofuranacetylchloride in 35 ml. of benzene is treated with 1.46 g. (16.4 mmoles) ofN,N-dimethylaminoethanol. After stirring for about 64 hours, the mixtureis washed twice with water, then the organic layer is evaporated toprovide a residue. The residue is dissolved in chloroform andchromatographed on silica gel. Infrared and nuclear magnetic resonancespectral analysis are consistent with the desired product,N,N-dimethylaminoethyl 2-nitro-3-phenyl-5-benzofuranacetate. This freebase is reacted with perchloric acid in diethyl ether to provide a solidproduct which is found to be perchloric acid salt.

    ______________________________________                                        Analysis:              % C    % H    % N                                      ______________________________________                                        Calculated for C.sub.20 H.sub.20 N.sub.2 O.sub.5 · HClO.sub.4        · 1/2H.sub.2 O:                                                                             50.7   4.4    5.9                                      Found:                 50.7   4.5    5.5                                      ______________________________________                                    

EXAMPLE 32

To a solution of 2.08 g. (8.25 mmoles) of 3-phenyl-7-benzofuranaceticacid in 10 ml. of benzene at 60° C. is slowly added small portions ofyellow mercuric oxide (1.45 g., 6.7 mmoles) and iodine (2.09 g., 8.25mmoles). After about two hours the mixture is filtered, then thefiltrate is evaporated to dryness to provide2-iodo-3-phenyl-7-benzofuranacetic acid.

To a solution of 2.2 g. (5.8 mmoles) of2-iodo-3-phenyl-7-benzofuranacetic acid, 1 g. (5.8 mmoles) ofcyclohexene and 175 ml. of chloroform is added 0.9 g. (10 mmoles) ofdinitrogen tetroxide in 15 ml. of chloroform. The mixture is stirred for20 hours, washed with water and made basic with sodium hydroxide. Thechloroform layer is acidified with hydrochloric acid, washed with watertwice and dried, then evaporated to provide2-nitro-3-phenyl-7-benzofuranacetic acid, identical to the sampleprepared in Example 2.

Using the method of Example 20, the following intermediate acids andfinal product compounds of Formula I are prepared starting with knwonsubstituted acetophenones or acetophenones prepared by known methods andethyl 4-hydroxyphenylacetate. The acetophenones are treated with oneequivalent of bromine in methylene chloride to obtain the requiredphenacylbromides.

    __________________________________________________________________________                    Melting Point of                     Melting Point            Example                                                                            Starting   Intermediate Acid                    of Product               No.  Acetophenone                                                                             (° C.)                                                                          Product                     (° C.)            __________________________________________________________________________    33                                                                                  ##STR22## 130-134                                                                                 ##STR23##                  164-167                  34                                                                                  ##STR24## --                                                                                      ##STR25##                  165-167                  35                                                                                  ##STR26## 138-140                                                                                 ##STR27##                  175-177                  36                                                                                  ##STR28## --                                                                                      ##STR29##                  185-187                  37                                                                                  ##STR30## --                                                                                      ##STR31##                  173-176                  38                                                                                  ##STR32## --                                                                                      ##STR33##                  176-177                  39                                                                                  ##STR34## 149-151                                                                                 ##STR35##                  193-195                  __________________________________________________________________________

example 40

equimolar amounts of 3-bromo-4-hydroxytoluene and α-bromoacetophenoneare refluxed in benzene in the presence of potassium carbonate toprovide α-(2-bromo-4-methylphenoxy)acetophenone in the usual manner.

A mixture of 700 g. of polyphosphoric acid and 100 g. ofα-(2-bromo-4-methylphenoxy)acetophenone is heated at 80°-90° C. for twohours, then poured into two liters of water with stirring. Chloroform (1liter) is added, and the phases are separated. The organic layer iswashed with water, dried, then evaporated to provide7-bromo-5-methyl-3-phenylbenzofuran as a brown oil.

A solution of 86.6 g. (0.30 mole) of 7-bromo-5-methyl-3-phenylbenzofuranin 600 ml. of dichloromethane is treated dropwise over 45 minutes with47.9 g. (0.30 mole) of bromine. After stirring one additional hour, themixture is washed once with water (300 ml.) and thrice with 300 ml.portions of saturated sodium bicarbonate solution, dried, thenevaporated to provide 2,7-dibromo-5-methyl-3-phenylbenzofuran as an oilwhich crystallizes from hexane.

A mixture containing 68.7 g. (0.19 mole) of2,7-dibromo-5-methyl-3-phenylbenzofuran and 35.5 g. (0.19 mole) ofN-bromosuccinimide in one liter of carbon tetrachloride is irradiatedwith a bulb simulating sunlight for two hours. An additional 10 g. ofN-bromosuccinimide is added, and irradiation is continued for one hour.The mixture is cooled and filtered. The filtrate is evaporated to abrown oil which crystallizes when triturated with hexane to providesolid 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran.

A solution of 17.8 g. (0.040 mole) of5-bromomethyl-2,7-dibromo-3-phenylbenzofuran in 150 ml. ofN,N-dimethylformamide, 2.0 g. (0.04 mole) of sodium cyanide and 15 ml.of water is heated on a steam bath for 1.5 hours. The mixture is pouredinto one liter of water and stirred for about 16 hours. The mixture isextracted with 500 ml. of ethyl acetate, the extracts washed with water,then dried. Evaporation followed by trituration with hexane-ethylacetate gives 5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran as a whitesolid.

A solution containing 11.1 g. (0.028 mole) of5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran, 10.7 g. (0.11 mole) ofdinitrogen tetroxide, 13.9 g. (0.11 mole) of cyclohexene-4-carboxylicacid and 1 g. of iodine in 500 ml. of chloroform is stirred at roomtemperature for 16 hours. An additional 13.9 g. ofcyclohexene-4-carboxylic acid and 10.7 g. of dinitrogen tetroxide areadded, and stirring is continued for 16 hours. The reaction is thentreated with 500 ml. of 10 percent sodium thiosulfate. The phases areseparated, and the organic phase is washed thrice with 250 ml. portionsof saturated sodium bicarbonate, once with 250 ml. of 3N hydrochloricacid and dried. Evaporation gives7-bromo-5-cyanomethyl-2-nitro-3-phenylbenzofuran as a yellow solid,recrystallized from ethyl acetate-hexane to give a sample for analysis.

    ______________________________________                                        Analysis:           % C     % H     % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.9 BrN.sub.2 O.sub.3 :                                               53.8    2.5     7.8                                       Found:              54.1    2.5     7.8                                       ______________________________________                                    

A mixture containing 2.0 g. of7-bromo-5-cyanomethyl-2-nitro-3-phenylbenzofuran and 30 ml. of 1:1sulfuric acid and water is stirred and heated at 150° C. for 1.5 hours.The mixture is then poured into 200 ml. of water. The solid is separatedby filtration, washed with water and dried. Recrystallization fromethanol gives yellow crystals of7-bromo-2-nitro-3-phenyl-5-benzofuranacetic acid, m.p. 125°-127° C.

    ______________________________________                                        Analysis:           % C     % H     % N                                       ______________________________________                                        Calculated for C.sub.16 H.sub.10 BrNO.sub.5 :                                                     51.1    2.7     3.7                                       Found:              50.6    2.7     4.0                                       ______________________________________                                    

EXAMPLE 41

Using the method described in Example 17, equimolar amounts of2-hydroxy-4-methoxytoluene and α-bromo-2-fluoroacetophenone are refluxedin benzene in the presence of potassium carbonate to provide2-fluoro-α-(2-methyl-5-methoxyphenoxy)acetophenone. Recrystallizationfrom cyclohexane provides a tan solid, m.p. 57°-58° C.

Cyclization of 16.4 g. of2-fluoro-α-(2-methyl-5-methoxyphenoxy)acetophenone is carried out inpolyphosphoric acid (120 g.) by heating at 60° C. for thirty minutes.The reaction mixture is poured into water and extracted with diethylether to provide 3-(2-fluorophenyl)-7-methyl-4-methoxybenzofuran as abrown oil. Its structure is confirmed by nuclear magnetic resonance andinfrared spectral analysis.

Using the method of Example 17,3-(2-fluorophenyl)-7-methyl-4-methoxybenzofuran is brominated withN-bromosuccinimide to provide2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran as an oil.Its structure is assigned on the basis of nuclear magnetic resonance andinfrared spectral analysis.

Using the method of Example 17,2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran is reactedwith sodium cyanide to provide2-bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran as a brownsolid after isolation by column chromatography.

2-Bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran ishydrolyzed by refluxing in ethanolic sodium hydroxide for 6 hours.Extraction with diethyl ether provides2-bromo-3-(2-fluorophenyl)-4-methoxy-7-benzofuranacetic acid as a whitesolid after recrystallization from benzene, m.p. 188°-191.5° C.

Using the method of Example 17,2-bromo-3-(2-fluorophenyl)-4-methoxy-7-benzofuranacetic acid is reactedwith dinitrogen tetroxide to provide3-(2-fluorophenyl)-4-methoxy-2-nitro-7-benzofuranacetic acid.Recrystallization of the acid from benzene provides yellow crystals,m.p. 185°-195° C.

    ______________________________________                                        Analysis:          % C      % H     % N                                       ______________________________________                                        Calculated for C.sub.17 H.sub.12 FNO.sub.6 :                                                     59.1     3.5     4.1                                       Found:             58.4     3.3     3.7                                       ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR36## wherein X ishalogen, lower alkyl, lower alkoxy, nitro, phenyl, cyano ortrifluoromethyl, n is zero, one or two, R is straight or branched chainalkylene of one to four carbon atoms or ethenylene, Y is methyl,methoxy, halogen or hydrogen or an ester, amide, acyl halide orpharmaceutically acceptable salt thereof, the ester and amide portionsof those derivatives containing not more than ten carbon atoms saidester being selected from the group consisting of lower alkyl esters,hydroxyalkyl esters, N,N-dialkylaminoalkyl esters, glyceryl esters andalkoxyalkyl esters and said amides being selected from the groupconsisting of N-unsubstituted amides, N-alkylamides, N-N-dialkylamides,dialkylaminoalkylamides, quaternary ammonium alkylamides,bis(2-hydroxyethyl) amides, amino acid amides, carboxyphenylamides,piperazinyl amides amino sugar amides, alkylsulfonamides,sulfoethylamides, sulfamoylphenylamides, and 5-tetrazolylamides.
 2. Acompound according to claim 1 wherein R is methylene.
 3. A compoundaccording to claim 1 wherein each X is fluorine and/or chlorine.
 4. Acompound according to claim 1 wherein the 4 position of the benzofuranmoiety is unsubstituted.
 5. An alkali metal salt according to claim 1.6. A compound according to claim 1 wherein n is zero.
 7. A compoundaccording to claim 1 wherein n is one.
 8. A compound of the formula##STR37## wherein X is halogen, lower alkyl, lower alkoxy, nitro,phenyl, cyano or trifluoromethyl, n is zero, one or two, R is straightor branched chain alkylene of one to four carbon atoms or ethenlene andY is methyl, methoxy, halogen or hydrogen.
 9. The compound2-nitro-3-phenyl-7-benzofuranacetic acid, according to claim
 8. 10. Thecompound 2-nitro-3-phenyl-6-benzofuranacetic acid according to claim 8.11. The compound 2-nitro-3-phenyl-5-benzofuranacetic acid according toclaim
 8. 12. The compound 2-nitro-3-phenyl-7-benzofuranacrylic acidaccording to claim
 8. 13. The compound2-nitro-3-phenyl-5-benzofuranpropionic acid according to claim
 8. 14.The compound 2-nitro-3-phenyl-7-benzofuranpropionic acid according toclaim
 8. 15. 3-(4'-Chlorophenyl)-2-nitro-5-benzofuranacetic acidaccording to claim
 8. 16. 3-(4'-Fluorophenyl)-2-nitro-7-benzofuranaceticacid according to claim
 8. 17.3-(4'-Chlorophenyl)-2-nitro-7-benzofuranacetic acid according to claim8.
 18. A lower alkyl ester according to claim
 1. 19. A hydroxyalkylester according to claim
 1. 20. An N,N-dialkylaminoalkyl ester accordingto claim
 1. 21. A glyceryl ester according to claim
 1. 22. Analkoxyalkyl ester according to claim
 1. 23. An N-unsubstituted amideaccording to claim
 1. 24. An N-alkylamide according to claim
 1. 25. AnN,N-dialkylamide according to claim
 1. 26. A dialkylaminoalkylamideaccording to claim
 1. 27. A quaternary ammonium alkylamide according toclaim
 1. 28. A bis(2-hydroxyethyl)amide according to claim
 1. 29. Anamino acid amide according to claim
 1. 30. A carboxyphenylamideaccording to claim
 1. 31. A piperazinyl amide according to claim
 1. 32.An amino sugar amide according to claim
 1. 33. An alkylsulfonamideaccording to claim
 1. 34. A sulfoethylamide according to claim
 1. 35. Asulfamoylphenylamide according to claim
 1. 36. A 5-tetrazolylamideaccording to claim
 1. 37. A method for arresting or inhibiting thegrowth of microorganisms comprising contacting microorganisms with acompound according to claim 1 in an amount sufficient to inhibit thegrowth of said microorganisms.
 38. A method according to claim 37 forarresting or inhibiting the growth of bacteria.
 39. A method forarresting or inhibiting the growth of trichomonads comprising contactingtrichomonads with a compound according to claim 1 in an amountsufficient to arrest or inhibit the growth of said trichomonads.
 40. Anantimicrobial composition comprising an antimicrobially effective amountof a compound according to claim 1 dispersed in a pharmaceuticallyacceptable extending medium.